Immune reconstitution and treatment response in multiple sclerosis following alemtuzumab Neil P. Robertson and Neil J. Scolding Neurology 2014;82;2150-2151 Published Online before print May 16, 2014 DOI 10.1212/WNL.0000000000000530 This information is current as of May 16, 2014
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/82/24/2150.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Immune reconstitution and treatment response in multiple sclerosis following alemtuzumab Neil P. Robertson, MD Neil J. Scolding, PhD
Correspondence to Dr. Robertson: [email protected] Neurology® 2014;82:2150–2151
Monoclonal antibodies have rapidly developed as an important therapeutic strategy in multiple sclerosis (MS). As a result of an improved understanding of pathogenesis, a number of agents are now in the latter stages of development, which may allow a more targeted approach to forms of this disease resistant to other treatments. Alemtuzumab is the second to emerge for treatment of relapsing MS and has had a long and occasionally painful evolution toward wider availability. Even now it continues to court controversy, having been approved for use in Europe but, to the dismay of many specialists, let alone patients, having so far been denied a license in the United States, the US Food and Drug Administration (FDA) citing concerns about blinding in trial designs and frequency of adverse events.1,2 Against an active comparator in 1 phase II and 2 phase III studies, alemtuzumab demonstrated a reduction in the risk of relapse and sustained accumulation of disability of more than 70% at 3 years, with sustained efficacy at 5 years.3 Its mode of action, dosing regimen, and striking durability of effect are novel and have contributed some unique insights into disease pathogenesis.4 Unusually, its use has evolved, particularly in the United Kingdom, outside of clinical trials5 as a result of convincing phase II results combined with its common availability (as a licensed treatment for certain leukemias). However, despite its marked efficacy and durability of effect in most patients, clinicians who use alemtuzumab are also aware of the adverse effects of treatment-related autoimmune diseases (which occur in approximately 30% of patients) as well as a small number of patients whose disease continues unabated despite treatment. This raises the obvious question as to whether nonresponders or those at high risk of autoimmune disease can be identified at an early stage, therefore avoiding risks of treatment or alternatively identifying those patients who require early retreatment to prevent disease reactivation and the risk of development of further fixed disability. The principal measurable effect of alemtuzumab as an anti-CD52 antibody is a rapid, profound, and
prolonged lymphopenia, the result of complementmediated lysis of circulating lymphocytes, but importantly not of hematopoietic stem cells. The infrequent dosing regimen then allows subsequent immune reconstitution6 that demonstrates temporal variability among lymphocyte subsets and may allow for a beneficial reconfiguring of the immune system, a likely substrate for its clinical effect, and also provides an attractive focus for investigation as a biomarker of treatment response. In a previous article in Neurology®, Cossburn et al.7 suggested that an accelerated recovery of CD41 cells could predict disease activity and that CD41 counts ,388.5 3 106 cells/mL predicted MRI stability. However, in a more detailed analysis published in this issue of Neurology by Kousin-Ezewu et al.,8 these initial observations could not be confirmed. There are differences between the studies that may explain the conflicting results. Both employed local cohorts but these differed in a number of characteristics. The most important was cohort size (56 vs 108) and length of follow-up (40 vs 99 months), which for the present study allowed 52% of patients to express disease activity but only 8/56 (14%) of the cohort reported by Cossburn et al., leaving the latter study prone to the impact of outliers. In addition, the present study examined data derived from a subset of the CAMMS 223, CAMMS 224, or SM3 studies. CAMMS223 key eligibility criteria were disease onset within 3 years, $2 clinical relapses during the previous 2 years, and a score of 3 or less on the Expanded Disability Status Scale (EDSS). Patients were included in CAMMS 224 and SM3 if they had at least 1 relapse in the previous year, an EDSS score of 6.0 or less, and disease duration of less than 10 years. In contrast, the cohort reported by Cossburn et al. were largely treatment-naive patients with onset within 5 years of first treatment and rapidly evolving MS, with high relapse rates (mean annualized relapse rate 2.6) and evidence of gadolinium-enhancing MRI brain activity. Other differences between the studies include the variability in EDSS outcomes, use of blinded vs unblinded assessors, and frequency and
See page 2158 From the Department of Neurology (N.P.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; and the Institute of Clinical Neurosciences (N.J.S.), University of Bristol, Frenchay Hospital, UK. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 2150
© 2014 American Academy of Neurology
availability of MRI data. Finally, although the infrequent dosing may represent a distinct advantage, it inevitably affects analysis since only patients demonstrating new disease activity are retreated. KousinEzewu et al. also suggest that the conflicting results may be related to differences in statistical methodology: Cossburn at al. compared post cycle 2 CD41 counts in clinically stable patients with those who had evidence of clinical or subclinical disease activity from time of most recent treatment, which included post cycle 3 CD41 counts. This approach assumes that lymphocyte reconstitution is identical between cycles, which may not be the case and may have led to falsepositive results. This issue was overcome in the present study by examining lymphocyte reconstitution and disease activity after and within each treatment cycle, although even this may be a flawed approach since intervals between retreatment for individual patients are highly variable and statistical analysis problematic. Whether these or other reasons explain the discrepancy is unclear, but the conclusion seems sound: there is currently insufficient evidence to employ absolute CD41 counts as a biomarker of treatment response. Therefore, one dilemma that will continue to face clinicians choosing to use alemtuzumab is that, after the standard 2 treatment cycles, it remains unclear whether redosing is beneficial and to what extent selected clinical events, disability progression, or MRI data should prompt retreatment—in some cases many years after the index treatment. Despite the conflicting results, the pace and nature of lymphocyte reconstitution remains an attractive target for biomarker investigation. However, whether examination restricted to standard subsets will provide a clear understanding of treatment response is unclear and may prove to be too simplistic. The continually evolving advances in cellular markers may yet unravel variability and durability of response in individual patients and also provide further important insights into disease pathogenesis; further investigation is therefore warranted. At present, the response to and continuing need for alemtuzumab, as with similarly acting or other disease-modifying treatments, remains unpredictable; the identification of validated and reproducible biomarkers in the management of MS remains elusive.
It is remarkable, however, that these considerations currently can be of no practical interest to USbased physicians. Notwithstanding positive licensing decisions in Australia, the European Union, Mexico, and Canada, the FDA has demanded further trials. To those of us somewhat incredulously observing from afar, it seems inconceivable that such a powerful and valuable new component of our MS therapeutic armamentarium can continue to be denied to US patients. AUTHOR CONTRIBUTIONS Neil P. Robertson: drafting/revising the manuscript. Neil Scolding: drafting/revising the manuscript, analysis or interpretation of data.
STUDY FUNDING No targeted funding reported.
DISCLOSURE N. Robertson has received consulting and lecture fees from Genzyme, lecture fees from Merck Serono, and research support paid to his institution from Genzyme. N. Scolding has received research support from Genzyme-Sanofi, Merck Serono, Biogen, and Novartis. Go to Neurology. org for full disclosures.
REFERENCES 1. Cossburn M, Pace AA, Jones J, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 2011;77:573–579. 2. Coles AJ, Wing M, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999;354:1691–1695. 3. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012;78:1069–1078. 4. Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46: 296–304. 5. Hirst CL, Pace A, Pickersgill TP, et al. Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis. J Neurol 2008;255:231–238. 6. Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005;35:3332–3342. 7. Cossburn MD, Harding K, Ingram G, et al. Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis. Neurology 2013;80: 55–61. 8. Kousin-Ezewu O, Azzopardi L, Parker RA, et al. Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity. Neurology 2014;82:2158–2164.
Neurology 82
June 17, 2014
2151
Immune reconstitution and treatment response in multiple sclerosis following alemtuzumab Neil P. Robertson and Neil J. Scolding Neurology 2014;82;2150-2151 Published Online before print May 16, 2014 DOI 10.1212/WNL.0000000000000530 This information is current as of May 16, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/24/2150.full.html
References
This article cites 8 articles, 3 of which you can access for free at: http://www.neurology.org/content/82/24/2150.full.html##ref-list1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Autoimmune diseases http://www.neurology.org//cgi/collection/autoimmune_diseases Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.neurology.org/content/82/24/2150.full.html
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2014 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Immune reconstitution and treatment response in multiple sclerosis following alemtuzumab Neil P. Robertson, MD Neil J. Scolding, PhD
Correspondence to Dr. Robertson: [email protected] Neurology® 2014;82:2150–2151
Monoclonal antibodies have rapidly developed as an important therapeutic strategy in multiple sclerosis (MS). As a result of an improved understanding of pathogenesis, a number of agents are now in the latter stages of development, which may allow a more targeted approach to forms of this disease resistant to other treatments. Alemtuzumab is the second to emerge for treatment of relapsing MS and has had a long and occasionally painful evolution toward wider availability. Even now it continues to court controversy, having been approved for use in Europe but, to the dismay of many specialists, let alone patients, having so far been denied a license in the United States, the US Food and Drug Administration (FDA) citing concerns about blinding in trial designs and frequency of adverse events.1,2 Against an active comparator in 1 phase II and 2 phase III studies, alemtuzumab demonstrated a reduction in the risk of relapse and sustained accumulation of disability of more than 70% at 3 years, with sustained efficacy at 5 years.3 Its mode of action, dosing regimen, and striking durability of effect are novel and have contributed some unique insights into disease pathogenesis.4 Unusually, its use has evolved, particularly in the United Kingdom, outside of clinical trials5 as a result of convincing phase II results combined with its common availability (as a licensed treatment for certain leukemias). However, despite its marked efficacy and durability of effect in most patients, clinicians who use alemtuzumab are also aware of the adverse effects of treatment-related autoimmune diseases (which occur in approximately 30% of patients) as well as a small number of patients whose disease continues unabated despite treatment. This raises the obvious question as to whether nonresponders or those at high risk of autoimmune disease can be identified at an early stage, therefore avoiding risks of treatment or alternatively identifying those patients who require early retreatment to prevent disease reactivation and the risk of development of further fixed disability. The principal measurable effect of alemtuzumab as an anti-CD52 antibody is a rapid, profound, and
prolonged lymphopenia, the result of complementmediated lysis of circulating lymphocytes, but importantly not of hematopoietic stem cells. The infrequent dosing regimen then allows subsequent immune reconstitution6 that demonstrates temporal variability among lymphocyte subsets and may allow for a beneficial reconfiguring of the immune system, a likely substrate for its clinical effect, and also provides an attractive focus for investigation as a biomarker of treatment response. In a previous article in Neurology®, Cossburn et al.7 suggested that an accelerated recovery of CD41 cells could predict disease activity and that CD41 counts ,388.5 3 106 cells/mL predicted MRI stability. However, in a more detailed analysis published in this issue of Neurology by Kousin-Ezewu et al.,8 these initial observations could not be confirmed. There are differences between the studies that may explain the conflicting results. Both employed local cohorts but these differed in a number of characteristics. The most important was cohort size (56 vs 108) and length of follow-up (40 vs 99 months), which for the present study allowed 52% of patients to express disease activity but only 8/56 (14%) of the cohort reported by Cossburn et al., leaving the latter study prone to the impact of outliers. In addition, the present study examined data derived from a subset of the CAMMS 223, CAMMS 224, or SM3 studies. CAMMS223 key eligibility criteria were disease onset within 3 years, $2 clinical relapses during the previous 2 years, and a score of 3 or less on the Expanded Disability Status Scale (EDSS). Patients were included in CAMMS 224 and SM3 if they had at least 1 relapse in the previous year, an EDSS score of 6.0 or less, and disease duration of less than 10 years. In contrast, the cohort reported by Cossburn et al. were largely treatment-naive patients with onset within 5 years of first treatment and rapidly evolving MS, with high relapse rates (mean annualized relapse rate 2.6) and evidence of gadolinium-enhancing MRI brain activity. Other differences between the studies include the variability in EDSS outcomes, use of blinded vs unblinded assessors, and frequency and
See page 2158 From the Department of Neurology (N.P.R.), Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, University Hospital of Wales; and the Institute of Clinical Neurosciences (N.J.S.), University of Bristol, Frenchay Hospital, UK. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial. 2150
© 2014 American Academy of Neurology
availability of MRI data. Finally, although the infrequent dosing may represent a distinct advantage, it inevitably affects analysis since only patients demonstrating new disease activity are retreated. KousinEzewu et al. also suggest that the conflicting results may be related to differences in statistical methodology: Cossburn at al. compared post cycle 2 CD41 counts in clinically stable patients with those who had evidence of clinical or subclinical disease activity from time of most recent treatment, which included post cycle 3 CD41 counts. This approach assumes that lymphocyte reconstitution is identical between cycles, which may not be the case and may have led to falsepositive results. This issue was overcome in the present study by examining lymphocyte reconstitution and disease activity after and within each treatment cycle, although even this may be a flawed approach since intervals between retreatment for individual patients are highly variable and statistical analysis problematic. Whether these or other reasons explain the discrepancy is unclear, but the conclusion seems sound: there is currently insufficient evidence to employ absolute CD41 counts as a biomarker of treatment response. Therefore, one dilemma that will continue to face clinicians choosing to use alemtuzumab is that, after the standard 2 treatment cycles, it remains unclear whether redosing is beneficial and to what extent selected clinical events, disability progression, or MRI data should prompt retreatment—in some cases many years after the index treatment. Despite the conflicting results, the pace and nature of lymphocyte reconstitution remains an attractive target for biomarker investigation. However, whether examination restricted to standard subsets will provide a clear understanding of treatment response is unclear and may prove to be too simplistic. The continually evolving advances in cellular markers may yet unravel variability and durability of response in individual patients and also provide further important insights into disease pathogenesis; further investigation is therefore warranted. At present, the response to and continuing need for alemtuzumab, as with similarly acting or other disease-modifying treatments, remains unpredictable; the identification of validated and reproducible biomarkers in the management of MS remains elusive.
It is remarkable, however, that these considerations currently can be of no practical interest to USbased physicians. Notwithstanding positive licensing decisions in Australia, the European Union, Mexico, and Canada, the FDA has demanded further trials. To those of us somewhat incredulously observing from afar, it seems inconceivable that such a powerful and valuable new component of our MS therapeutic armamentarium can continue to be denied to US patients. AUTHOR CONTRIBUTIONS Neil P. Robertson: drafting/revising the manuscript. Neil Scolding: drafting/revising the manuscript, analysis or interpretation of data.
STUDY FUNDING No targeted funding reported.
DISCLOSURE N. Robertson has received consulting and lecture fees from Genzyme, lecture fees from Merck Serono, and research support paid to his institution from Genzyme. N. Scolding has received research support from Genzyme-Sanofi, Merck Serono, Biogen, and Novartis. Go to Neurology. org for full disclosures.
REFERENCES 1. Cossburn M, Pace AA, Jones J, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology 2011;77:573–579. 2. Coles AJ, Wing M, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999;354:1691–1695. 3. Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012;78:1069–1078. 4. Coles AJ, Wing MG, Molyneux P, et al. Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis. Ann Neurol 1999;46: 296–304. 5. Hirst CL, Pace A, Pickersgill TP, et al. Campath 1-H treatment in patients with aggressive relapsing remitting multiple sclerosis. J Neurol 2008;255:231–238. 6. Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005;35:3332–3342. 7. Cossburn MD, Harding K, Ingram G, et al. Clinical relevance of differential lymphocyte recovery after alemtuzumab therapy for multiple sclerosis. Neurology 2013;80: 55–61. 8. Kousin-Ezewu O, Azzopardi L, Parker RA, et al. Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity. Neurology 2014;82:2158–2164.
Neurology 82
June 17, 2014
2151
Immune reconstitution and treatment response in multiple sclerosis following alemtuzumab Neil P. Robertson and Neil J. Scolding Neurology 2014;82;2150-2151 Published Online before print May 16, 2014 DOI 10.1212/WNL.0000000000000530 This information is current as of May 16, 2014 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/82/24/2150.full.html
References
This article cites 8 articles, 3 of which you can access for free at: http://www.neurology.org/content/82/24/2150.full.html##ref-list1
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Autoimmune diseases http://www.neurology.org//cgi/collection/autoimmune_diseases Multiple sclerosis http://www.neurology.org//cgi/collection/multiple_sclerosis
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
